Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing.

摘要: Drug-induced torsade de pointes (TdP) has proved to be a significant iatro-genic cause of morbidity and mortality major reason for the withdrawal number drugs from market in recent times. Enzymes that metabolise many these potassium channels are responsible cardiac repolarisation display genetic polymorphisms. Anecdotal reports have suggested cases drug-induced TdP, there may concealed defect either enzymes or channels, giving rise high plasma drug concentrations diminished reserve, respectively. The presence defects predispose patient potentially fatal adverse reaction, even at therapeutic dosages QT-prolonging absence other risk factors. Advances pharmacogenetics metabolising pharmacological targets, together with prospects rapid inexpensive genotyping procedures, promise individualise improve benefit/risk ratio therapy potential TdP. qualitative quantitative contributions clinical TdP unclear because not all patients routinely genotyped some relevant mutations still remain discovered. There regulatory guidelines recommend strategies aimed uncovering associated new chemical entities during their development. also integrating this process. This paper proposes strategy into development programmes optimise association studies correlating traits endpoints interest, namely failure efficacy abnormalities. Until is carefully integrated phases large-scale undertaken post-marketing use determine components involved induction routine remains unrealistic. Even without pharmacogenetic data, can already greatly minimised. Clinically, substantial proportion due usual factors inhibit metabolism. Therefore, choosing lowest effective dose identifying non-genetic important means minimising In view common secondary pharmacology shared by drugs, standard set contraindications warnings evolved over last decade. These include pharmacokinetic pharmacodynamic interactions. Among latter, more ones bradycardia, electrolyte imbalance, disease co-administration two drugs. principle, if large scale prospective demonstrate component, pharmacogenetically driven prescribing ought reduce further. However, any benefits will squandered reduction physicians do follow monitoring recommendations.